RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans

Son, Heehwa G.; Seo, Mihwa; Ham, Seokjin; Hwang, Wooseon; Lee, Dong-Yeop; An, Seon Woo A.; Artan, Murat; Seo, Keunhee; Kaletsky, Rachel; Arey, Rachel N.; Ryu, Youngjae; Ha, Chang Man; Kim, Yoon Ki; Murphy, Coleen T.; Roh, Tae-Young; Nam, Hong Gil; Lee, Seung-Jae

doi:10.1038/ncomms14749

Cited by 69 publications

(70 citation statements)

References 51 publications

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“…This would have important consequences for the removal of aberrant mRNAs and could contribute to the decline of nonsense-mediated decay observed with age. 38 Significantly the function of other membrane-less structures such as the nucleolus are likely to be negatively affected by the aggregation of RBPs with LC prion-like domains. For instance, we identified that the nucleolus RBP Fibrillarin (FIB-1) was highly prone to aggregate with age.…”

Section: Discussionmentioning

confidence: 99%

More stressed out with age? Check your RNA granule aggregation

Lechler

David

2017

Prion

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ABSTRACT. Low complexity (LC) prion-like domains are over-represented among RNAbinding proteins (RBPs) and contribute to the dynamic nature of RNA granules. Importantly, several neurodegenerative diseases are characterized by cytoplasmic "solid" aggregates formed by mainly nuclear RBPs harboring LC prion-like domains. Although RBP aggregation in disease has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. Our recent study revealed that RNA granule components including 2 key stress granule RBPs with LC prion-like domains, PAB-1 and TIAR-2, aggregate in aged Caenorhabditis elegans in the absence of disease. Here we present new evidence showing that sustained stress granule formation triggers RBP aggregation. In addition, we demonstrate that mild chronic stress during aging promotes mislocalization of nuclear RBPs. We discuss the consequences of aberrant interactions between age-related RBP aggregation and diseaseassociated RBP aggregation. In particular, we show that FUST-1 and PAB-1 co-localize in aberrant cytoplasmic accumulations. Significantly, long-lived animals with reduced insulin/IGF-1 signaling abrogate stress granule RBP aggregation through activation of the transcription factors HSF-1 and DAF-16. We evaluate the different mechanisms that could maintain dynamic Ó 2017 Deutsches Zentrum f€ ur Neurodegenerative Erkrankungen e. V. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 313 Prion, 11:313-322, 2017 Published with license by Taylor & Francis ISSN: 1933-68961933-690X online DOI: 10.1080/19336896.2017 stress granules. Together these findings highlight how changes with age could contribute to pathogenesis in neurodegenerative diseases and disruption of RNA homeostasis.

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Section: Discussionmentioning

confidence: 99%

More stressed out with age? Check your RNA granule aggregation

Lechler

David

2017

Prion

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“…Lifespan assays. Lifespan assays were conducted as previously described (Son et al, 2017). Young (day 0) adult worms that were grown on control RNAi and daf-2…”

Section: Rnai Inductionmentioning

confidence: 99%

“…RNA extraction and quantitative RT-PCR. RNA extraction and qRT-PCR were performed as previously described with minor modifications (Son et al, 2017). When worms that were fed with OP50 or RNAi bacteria reached L4 or young adult stage (day 0), 50 μM FUdR was supplemented.…”

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confidence: 99%

Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit

Lee

Jeong

Hwang

et al. 2019

Preprint

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Immunosenescence is considered an inevitable decline in immune function during aging. Here we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and rejuvenates immunity in C. elegans. We find that p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunosenescence, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The upregulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn downregulates INS-7, an agonistic insulinlike peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via the upregulation of anti-aging transcription factors that modulate an endocrine insulinlike peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies for human immune rejuvenation. Results Genetic inhibition of the DAF-2/insulin/IGF-1 receptor improves immunity in aged wormsWe wondered whether the rates of immunosenescence were proportionally affected by genetic mutations that promote longevity. Thus, we measured immunosenescence in various long-lived animals, including IIS-defective daf-2, sensory-defective osm-5, germline-deficient glp-1, dietary restriction mimetic eat-2, and mitochondrial respiration-impaired isp-1 mutants. Similar to the wild-type counterparts (Laws et al., 2004; Youngman et al., 2011), osm-5, glp-1, and eat-2 mutants exhibited an age-dependent increase in susceptibility to Pseudomonas aeruginosa (PA14) infection ( Figures 1A-1E). Old isp-1 mutants displayed susceptibility to PA14 infection that was comparable to that of young animals; however, their overall survival rate was lower than that of wild-type worms ( Figures 1A and 1F). Surprisingly, old (day 9) daf-2 mutants displayed substantially enhanced survival upon PA14 infection compared with young (day 1) daf-2 mutants and wildtype worms (Figures 1A and 1G). Consistent with daf-2 mutant data, old (day 9) daf-2(RNAi) worms also displayed enhanced PA14 resistance ( Figure 1H), without defects in feeding rates ( Figures 1I). Old (day 9) daf-2 mutant worms also survived longer than did young worms after infection with PAO1, another P. aeruginosa strain ( Figures 1J and 1K). These data suggest that genetic inhibition of DAF-2 confers sustained immunocompetence against P. aeruginosa in old age, which was different from other longevity interventions.

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“…In C. elegans, NMD is governed by the activity of several genes, including smg-1/2/3/4/5/6/7, which are responsible for the detection of aberrant transcripts, releasing the stalled ribosome, and degrading the transcript (Hug et al, 2016). Given that the translation of NMD prone transcripts appeared to be regulated by DR and that NMD has been shown to play a role in ILS mediated longevity (Son et al, 2017), we hypothesized that NMD plays a role in DR induced longevity. We tested the importance of NMD in longevity using mutants defective in smg-1/2/3/4/5/6/7 subject to AL or DR starting at adulthood.…”

Section: Nmd Genes Smg-6 and Smg-7 Are Required For Dr-mediated Lifesmentioning

confidence: 99%

“…The gene F13G3.6 was investigated as it was reported to have a PTC bearing isoform whose expression is dependent on the activity of the NMD gene smg-2 in C. elegans (Son et al, 2017). This gene is similar to human B3GNTL1, which plays a role in elongating N-glycans on mucin proteins.…”

Section: Intron Retention Increases Under Drmentioning

confidence: 99%

Dietary restriction induces post-transcriptional regulation of longevity genes

Rollins

Snow

Kapahi

et al. 2019

Preprint

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Dietary restriction increases lifespan through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of C. elegans subjected to dietary restriction. Transcription of muscle regulatory and structural genes increased, while increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of post-transcriptional regulation identified putative roles for RNA binding proteins, RNA editing, microRNA, alternative splicing, and nonsense mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate lifespan. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally downregulated genes. Furthermore, 3' UTR editing and intron retention increase under dietary restriction and correlate with diminished translation, while trans-spliced genes are refractory to reduced translation efficiency compared to messages with the native 5' UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense mediated decay targets, are required for increased lifespan under dietary restriction.

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RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans

Cited by 69 publications

References 51 publications

More stressed out with age? Check your RNA granule aggregation

More stressed out with age? Check your RNA granule aggregation

Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit

Dietary restriction induces post-transcriptional regulation of longevity genes

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